Hypercapnia, the elevation of PCO2 in blood and tissue, commonly occurs in advanced COPD and in acute respiratory failure. Patients with COPD frequently develop bacterial and viral lung infections, including influenza, and hypercapnia is a risk factor for mortality in such individuals. We have shown that hypercapnia suppresses transcription of multiple NF-?B-regulated innate immune genes required for host defense and inhibits phagocytosis and autophagy-mediated bacterial killing by macrophages (Ms). Moreover, we found that hypercapnia increases mortality due to bacterial infections in both mice and Drosophila. These findings strongly suggest that hypercapnia is not simply a marker of advanced lung disease, but that it plays a causal role in poor clinical outcomes by suppressing immune function and increasing susceptibility to infection. The similarity of hypercapnia's effects in Drosophila and mammalian systems suggested that elevated CO2 inhibits innate immune gene expression by conserved pathway(s). Thus, we conducted a genome-wide RNAi screen in Drosophila and identified the zinc finger homeobox transcription factor, zfh2, as a candidate mediator of CO2's immunosuppressive effects. Notably, mutant Drosophila deficient in zfh2 were protected against the CO2-induced increase in mortality from bacterial infection. Next, we found that ZFHX3, a mammalian zfh2 ortholog, is expressed in Ms; that ZFHX3 binds in a CO2-sensitive manner to multiple hypercapnia-regulated M genes; and that siRNA knockdown of ZFHX3 blocked hypercapnic immune gene suppression. In preliminary experiments for the current application, we observed that hypercapnia inhibited LPS- and influenza A virus (IAV)-induced expression of type I interferon (IFN) pathway antiviral genes in human and mouse Ms. Notably, ZFHX3 bound IFN regulatory factors (IRFs) and NF-?B genes, and this binding was CO2-sensitive, suggesting that ZFHX3 mediates hypercapnia's effect on antiviral gene expression by blocking IRF- and NF-?B- activated transcription of IFN-? and IFN-?. We also found that hypercapnia suppressed IAV-induced autophagy, another antiviral pathway, and that this followed hypercapnia-induced increases in expression of the negative autophagy regulators, Bcl-2 and Bcl-xL, and activation of Akt. Finally, of critical importance, exposure to elevated CO2 enhanced IAV replication in Ms and other cells and increased the mortality of IAV infection in mice. The proposed studies will test the hypothesis that hypercapnia inhibits expression of IFN pathway antiviral genes via CO2-dependent changes in transcription mediated by ZFHX3; that hypercapnia inhibits influenza- induced autophagy via increased expression of Bcl-2 and Bcl-xL and activation of Akt; and that myeloid ZFHX3 deficiency or blocking hypercapnic inhibition of autophagy will decrease IAV-associated lung injury and mortality in mice. This investigation will define novel mechanisms by which elevated levels of CO2 suppress antiviral host defense, a previously-unrecognized adverse consequence of hypercapnia, and will lay the basis for future studies aimed at preventing hypercapnia-induced immunosuppression in patients with advanced lung disease.